PROJECT SUMMARY Traumatic brain injury (TBI) is a major cause of long-term disability in the United States. Although more individuals survive traumatic brain injury than in the past, the survivors endure residual physical, cognitive, emotional and/or behavioral impairments from the cascade of biochemical responses resulting from TBI. The etiology of secondary brain injury is multi-factorial, with a host of likely inter- related processes: mitochondrial energy failure, excessive generation of reactive oxygen species, activation of destructive enzymes such as poly (ADP-ribose) polymerase (PARP), membrane disruption, neuronal death, thrombosis due to intravascular coagulation in small vessels, increased synaptic concentrations of excitatory amino acids, and activation of innate inflammatory responses. As secondary brain injury is multi-factoral, pharmacological strategies of neuroprotection must include drugs that target multiple mechanisms of the secondary injury. Translation of positive pre-clinical experimental studies into large randomized, controlled trials has been uniformly negative. The reason for the failure of the trials is probably due to many factors also. Specifically relevant to this proposal, the pre-clinical studies often failed to optimize the dose and dosage regimen, doses were often administered at non-clinically relevant times, i.e. pre-injury or immediately after injury with an overall absence of pharmacokinetic data to guide rational dosing. The primary objective of the proposal is to determine the optimal multi-drug therapy to promote neurological recovery in an animal model of traumatic brain injury using behavioral, histological and gene expression markers of neuroprotection to select the drugs and maximize the dosage regiment 1) by identifying combination therapy that targets the maximum number of molecular, cellular and biochemical secondary effects of TBI based on the pharmacologic properties of the drugs and 2) by determining the optimal dosage regimen in animals which would correlate to the proposed treatment of TBI in humans based on pharmacokinetic properties, Optimization includes the time of first dose, the dosage interval and the duration of treatment.